Mitochondrial Mechanisms in Cerebral Vascular Control: Shared Signaling Pathways with Preconditioning

Busija, David W.; Katakam, Prasad V. G.

doi:10.1159/000360765

Cited by 50 publications

(46 citation statements)

References 134 publications

(207 reference statements)

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“…These findings confirm and extend our original observations with BMS and diazoxide in cerebral endothelial and vascular smooth muscle cells as well as in cultured neurons and astroglia and isolated mitochondria (20,22). The consistent results from our studies as well as several investigations by others clearly demonstrate our original finding that mitochondrial depolarization with agents such as BMS can occur without increasing intracellular or mitochondrial ROS (2,3,16,20,22,23). It is interesting that although diazoxide and BMS differ in their effect on mitochondrial ROS generation in various cell types we studied, they activate identical signaling events downstream of mitochondrial depolarization (3,15,16,20,22).…”

Section: Discussionsupporting

confidence: 91%

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Katakam

Dutta

Sure

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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-The diverse signaling events following mitochondrial depolarization in neurons are not clear. We examined for the first time the effects of mitochondrial depolarization on mitochondrial function, intracellular calcium, neuronal nitric oxide synthase (nNOS) activation, and nitric oxide (NO) production in cultured neurons and perivascular nerves. Cultured rat primary cortical neurons were studied on 7-10 days in vitro, and endothelium-denuded cerebral arteries of adult Sprague-Dawley rats were studied ex vivo. Diazoxide and BMS-191095 (BMS), activators of mitochondrial K ATP channels, depolarized mitochondria in cultured neurons and increased cytosolic calcium levels. However, the mitochondrial oxygen consumption rate was unaffected by mitochondrial depolarization. In addition, diazoxide and BMS not only increased the nNOS phosphorylation at positive regulatory serine 1417 but also decreased nNOS phosphorylation at negative regulatory serine 847. Furthermore, diazoxide and BMS increased NO production in cultured neurons measured with both fluorescence microscopy and electron spin resonance spectroscopy, which was sensitive to inhibition by the selective nNOS inhibitor 7-nitroindazole (7-NI). Diazoxide also protected cultured neurons against oxygen-glucose deprivation, which was blocked by NOS inhibition and rescued by NO donors. Finally, BMS induced vasodilation of endothelium denuded, freshly isolated cerebral arteries that was diminished by 7-NI and tetrodotoxin. Thus pharmacological depolarization of mitochondria promotes activation of nNOS leading to generation of NO in cultured neurons and endothelium-denuded arteries. Mitochondrial-induced NO production leads to increased cellular resistance to lethal stress by cultured neurons and to vasodilation of denuded cerebral arteries. MITOCHONDRIAL MEMBRANE POTENTIAL is a critical regulator of cellular activity and survival and is controlled by a variety of factors including the ATP-sensitive potassium (mitoK ATP ) channels located on the inner mitochondrial membrane (2). Pharmacological activators of mitoK ATP channels, such as BMS-191095 (BMS) and diazoxide, decrease the mitochondrial membrane potential by facilitating the influx of potassium from cytosol into the matrix (2). Signaling events following mitochondrial depolarization appear to be diverse in the various cell types comprising the neurovascular unit (cerebral vascular endothelium and smooth muscle, perivascular neurons, parenchymal neurons, and glia). Both BMS and diazoxide applications result in dilation of isolated cerebral arteries; however, individual effects on vascular smooth muscle and endothelium, which contribute to the overall vascular effect, are completely different (20,22,35,42). Thus BMS and diazoxide relax cerebral vascular smooth muscle cells via generation of localized calcium sparks by sarcoplasmic reticulum linked to mitochondrial depolarization, resulting in decreased global intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (20, 42). Conversely, mitochondrial depolarization in cerebral endothe...

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Section: Discussionsupporting

confidence: 91%

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Katakam

Dutta

Sure

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…For purposes of illustration, we have chosen representative images from different cell types of the neurovascular unit, which demonstrate the variety of mitochondrial numbers, morphology, locations, and relationships to other cellular structures. In particular, the mitochondrial features in cerebral arteries and brain parenchyma are similar to those published previously (14,116,131). Additionally, we have published examples of morphological features of isolated brain, liver and cardiac mitochondria, mitochondria in cultured and intact cortical neurons, mitochondria in cultured cerebral vascular endothelium as well as mitochondria in intact arteries from male and female rats and hearts from normal and IR rats (14,87,101,116,131,145).…”

Section: Mitochondrial Morphologysupporting

confidence: 76%

Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

Busija

Rutkai

Dutta

et al. 2016

Comprehensive Physiology

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Mitochondria not only produce energy in the form of ATP to support the activities of cells comprising the neurovascular unit, but mitochondrial events, such as depolarization and/or ROS release, also initiate signaling events which protect the endothelium and neurons against lethal stresses via pre-/postconditioning as well as promote changes in cerebral vascular tone. Mitochondrial depolarization in vascular smooth muscle (VSM), via pharmacological activation of the ATP-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels), leads to vasorelaxation through generation of calcium sparks by the sarcoplasmic reticulum and subsequent downstream signaling mechanisms. Increased release of ROS by mitochondria has similar effects. Relaxation of VSM can also be indirectly achieved via actions of nitric oxide (NO) and other vasoactive agents produced by endothelium, perivascular and parenchymal nerves, and astroglia following mitochondrial activation. Additionally, NO production following mitochondrial activation is involved in neuronal preconditioning. Cerebral arteries from female rats have greater mitochondrial mass and respiration and enhanced cerebral arterial dilation to mitochondrial activators. Preexisting chronic conditions such as insulin resistance and/or diabetes impair mitoKATP channel relaxation of cerebral arteries and preconditioning. Surprisingly, mitoKATP channel function after transient ischemia appears to be retained in the endothelium of large cerebral arteries despite generalized cerebral vascular dysfunction. Thus, mitochondrial mechanisms may represent the elusive signaling link between metabolic rate and blood flow as well as mediators of vascular change according to physiological status. Mitochondrial mechanisms are an important, but underutilized target for improving vascular function and decreasing brain injury in stroke patients. © 2016 American Physiological Society. Compr Physiol 6:1529-1548, 2016.

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“…We went on to demonstrate that eNOS in ZO arteries partly exists in an uncoupled state, contributing to increased ROS levels (29). Our laboratory previously demonstrated the importance of mitoK ATP channels in preconditioning and regulation of vascular tone (9,10,28,30,41). In the present study, treatment with DZ did not significantly affect any of the segments of mitochondrial respiration in either the ZL or ZO group.…”

Section: Discussionmentioning

confidence: 41%

The mitochondrial function of the cerebral vasculature in insulin-resistant Zucker obese rats

Merdžo

Rutkai

Tokes

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Little is known about mitochondrial functioning in the cerebral vasculature during insulin resistance (IR). We examined mitochondrial respiration in isolated cerebral arteries of male Zucker obese (ZO) rats and phenotypically normal Zucker lean (ZL) rats using the Seahorse XFe24 analyzer. We investigated mitochondrial morphology in cerebral blood vessels as well as mitochondrial and nonmitochondrial protein expression levels in cerebral arteries and microvessels. We also measured reactive oxygen species (ROS) levels in cerebral microvessels. Under basal conditions, the mitochondrial respiration components (nonmitochondrial respiration, basal respiration, ATP production, proton leak, and spare respiratory capacity) showed similar levels among the ZL and ZO groups with the exception of maximal respiration, which was higher in the ZO group. We examined the role of nitric oxide by measuring mitochondrial respiration following inhibition of nitric oxide synthase with Nω-nitro-l-arginine methyl ester (l-NAME) and mitochondrial activation after administration of diazoxide (DZ). Both ZL and ZO groups showed similar responses to these stimuli with minor variations. l-NAME significantly increased the proton leak, and DZ decreased nonmitochondrial respiration in the ZL group. Other components were not affected. Mitochondrial morphology and distribution within vascular smooth muscle and endothelium as well as mitochondrial protein levels were similar in the arteries and microvessels of both groups. Endothelial nitric oxide synthase (eNOS) and ROS levels were increased in cerebral microvessels of the ZO. Our study suggests that mitochondrial function is not significantly altered in the cerebral vasculature of young ZO rats, but increased ROS production might be due to increased eNOS in the cerebral microcirculation during IR.

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Mitochondrial Mechanisms in Cerebral Vascular Control: Shared Signaling Pathways with Preconditioning

Cited by 50 publications

References 134 publications

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

The mitochondrial function of the cerebral vasculature in insulin-resistant Zucker obese rats

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